The transcription factor Myc plays a role in regulating cell proliferation, the cell cycle, cell growth, angiogenesis, apoptosis, and oncogenesis. Myc's activity can increase in tumors as a consequence of mutations, chromosomal rearrangements, increased expression, or gene amplification (see, e.g., Nesbit, et al. (1999) Oncogene 18:3004-3016; Zeller, et al. (2001) J. Biol. Chem. 276:48285-48291; He, et al. (1998) Science 281:1509-1512; McMahon, et al. (1998) Cell 94:363-374; Erisman, et al. (1985) Mol. Cell Biol. 5:1969-1976; Rochlitz, et al. (1996). Oncology 53:448-454). Increased Myc levels have been found, for example, in breast cancer and prostate cancer (Liao, et al. (2000) Endocrine-Related Cancer 7:143-164; Jenkins, et al. (1997) Cancer Res. 57:524-531).
When Myc acts as a cell cycle regulator, it can promote entry of a cell into the cell cycle (Trumpp, et al. (2001) Nature 414:768-773; Holzel, et al. (2001) EMBO Reports 21:1125-1132; Bouchard, et al. (2001) Genes Devel. 15:2042-2047). Myc has been found to act in certain phases of the cell cycle, where cell cycle genes, e.g., cyclins and protein kinases, may be directly or indirectly regulated by Myc. Myc also regulates growth, as it plays a role in regulating genes required for protein synthesis, e.g., genes encoding transcription factors and ribosomal proteins (Greasley, et al. (2000) Nucleic Acids Res. 28:446-453); Zeller, et al. (2001) supra; Menssen, et al. (2002) Proc. Natl. Acad. Sci. USA 59:6274-6279). Myc regulates apoptosis, which can be impaired in cancer cells. Myc has been shown to regulate key apoptosis pathway proteins (Nesbit, et al. (1998) Blood 92:1003-1010).
Many diseases are associated with abnormal cell signaling triggered by Myc-mediated events described above, including proliferative diseases (e.g., cancer) and cardiovascular diseases. Accordingly, there is a need to identify Myc inhibitors useful as therapeutic agents and research tools.